Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH:22]1[C:32]2[CH2:31][NH:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[NH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.C1(C2C=CC(C(Cl)=O)=CC=2)CCCCC1>ClCCl.CN(C)C=O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:30]3[CH2:31][C:32]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[NH:27][C:28]4[CH:36]=[CH:35][CH:34]=[CH:33][C:29]3=4)=[O:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1ccc(C2CCCCC2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccccc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a suspension of 4-cyclohexylbenzoic acid (10.0 g) in dichloromethane (75 mL) was added oxalyl chloride (10.0 g) followed by N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature overnight and then all volatiles were removed in vacuo to provide the crude acid chloride (11.0 g). 5,11-Dihydro-10H-dibenzo[b,e][1,4]diazepine (1.96 g) in dichloromethane (50 mL) containing N,N-diisopropylethyl amine (1.3 g) was reacted with the crude 4-cyclohexylbenzoyl chloride prepared as described above (2.22 g). The reaction mixture was kept at room temperature overnight, then washed with water and saturated aqueous sodium bicarbonate. The solution was dried over anhydrous sodium sulfate and filtered through a short column of Magnesol® which was eluted with several additional volumes of dichloromethane. The total effluent was refluxed with the gradual addition of hexane until crystallization was noted. Cooling and filtration afforded the title compound as colorless crystals (1.28 g), m.p. 175-176° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](NC(C)(C)C)=[O:7])=[C:4]([CH2:15][CH2:16][OH:17])[C:3]=1[F:18].CC1C=CC(S(O)(=O)=O)=CC=1.C1COCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([F:18])=[C:4]2[C:5](=[CH:13][CH:14]=1)[C:6](=[O:7])[O:17][CH2:16][CH2:15]2
Reactant: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1OCCc2c1ccc(Br)c2F
Reaction time: 1 h

Procedure:
A solution of 4-bromo-N-tert-butyl-3-fluoro-2-(2-hydroxyethyl)benzamide. (1.8 g, 5.7 mmol) and TsOH (1.3 g, 6.9 mmol) in toluene (100 mL)/THF (10 mL) was heated to reflux. After 1 h, TLC and LC/MS analysis indicated complete conversion. The solution was concentrated to dryness followed by dilution with Et2O (150 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated affording the title compound: LC-MS: m/z 246.92 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[Cu](C#N)[C:13]#[N:14].C(OC(C)C)(=O)C>C(#N)CC.[Cl-].[Na+].O>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:13]#[N:14])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: CCC#N
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
The compound of Step 1 (1 eq) was suspended in propionitrile (3 vol). Copper cyanide (1.1 eq) was added and the mixture was heated to 90° C. and aged for about 17 h. The reaction mixture was cooled to room temperature and isopropyl acetate (12 vol) and saturated brine (8 vol) were added. The mixture was stirred for 15 min and the layers were cut. The top organic layer was washed with brine (4×6 vol). The batch concentrated under reduced pressure to yield the desired product.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[I:7][CH2:8][CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CCOCC>[I:7][CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCCI
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: ICCOC1CCCCO1
Reaction time: 1 h

Procedure:
Freshly distilled dihydropyran (Aldrich, 59.0 g, 0.7 mol) was added dropwise to a cooled solution of 2-iodoethanol (Aldrich, 98 g, 0.57 mol) in Et2O (1 L) containing 0.1 g of p-toluenesulfonic acid (Eastman). The solution was then stirred for 1 h at 5°. Solid K2CO3 (Mallinckrodt, 5 g) was then added to the reaction mixture and the resulting suspension stirred an additional 1 h at RT. The reaction was then filtered and the remaining solid washed with Et2O (1 L). The organic solutions were combined and concentrated rotary evaporation (in a flask washed with 1% NEt3 in H2O). The crude 2-(2-iodoethoxy)-tetrahydro-2-H-pyran (~100 g, 68.9%) was used without further purification.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[N:5]1([CH2:11][CH2:12][C:13]([NH:15][NH2:16])=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1>CCO>[CH3:1][N:2]1[C:13]([CH2:12][CH2:11][N:5]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[N:15][N:16]=[C:3]1[SH:4]
Reactant: NNC(=O)CCN1CCOCC1
Reactant: CN=C=S
Solvent: CCO
Product: Cn1c(S)nnc1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Prepared according to a procedure reported for related compounds: Henichart, J. P. et al. J. Het Chem. 1977, 14, 615. Methyl isothiocyanate (9.08 g, 0.124 mol) in EtOH (50 mL) was added at room temperature to a stirred solution of 3-morpholin-4-ylpropanohydrazide (21.5 g, 0.124 mol) in EtOH (200 mL). The mixture was refluxed for 8 h, then removed from heat and stirred at room temperature for 16 h. The EtOh was removed under reduced pressure to give the crude material as a yellow oil. The oil was purified by column chromatography through silica gel, eluting with CH2Cl2/MeOH to afford the title compound. (6 g, 21.2%) 1H NMR (DMSO-d6) d 2.42 (m, 4H) 2.64 (m, 2H) 2.85 (m, 2H, 3.43 (s, 3H) 3.55 (m, 4H) 13.47 (s, 1H). MS (APCI) calcd for C9H16N4OS: 228.32; found (M−H+) 227.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.O=S(Cl)[Cl:16].CN(C=O)C>C(Cl)Cl>[Cl:16][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1CCl
Reaction time: 16 h
Yield: 92.1 %

Procedure:
To a solution of (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (14.5 g, 71 mmol) in 100 mL CH2Cl2 at room temperature under argon was added SOCl2 (16.8 g, 142 mmol), followed by about 1.5 mL DMF, which was added to re-dissolve the rapidly formed, precipitating hydrochloride salt of the starting material. The resulting reaction mixture was stirred for 16 h. HPLC/MS analysis indicated that the reaction was complete. Solvent was evaporated under vacuum. The resulting residue was dissolved in 200 mL Et2O, and the resulting solution was washed with 10% aqueous sodium carbonate solution (100 mL), then brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 13.7 g of the title compound as a tan oil, which was greater than 98% pure. HPLC/MS: retention time=2.9 min, [M+H]+=210.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[C:7]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[CH3:11])=[O:5].[BH4-].[Na+].O>O1CCCC1.CO>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH:4]([OH:5])[C:6]1[C:7]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[CH3:11]
Reactant: COC(=O)c1ccc2sc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2sc(C)c(C(O)c3ccc(Cl)cc3Cl)c2c1
Reaction time: 0.67 h
Yield: 96.3 %

Procedure:
3-(2,4-Dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylbenzo[b]-thiophene (600 mg, 1.58 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (1 ml), and sodium borohydride (72 mg, 1.9 mmol) was added thereto under ice-cooling. The mixture was stirred for 40 min under ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the objective compound (580 mg, 96%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1)([CH3:15])[CH3:14].C(N(CC)CC)C>C(O)C>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[NH:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=1
Reactant: Fc1cccc2c(Cl)ncnc12
Reactant: CC(C)c1ccc(CCN)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(CCNc2ncnc3c(F)cccc23)cc1

Procedure:
A mixture of 2 g of 4-chloro-8-fluoroquinazoline, 1.94 g of 2-[4-(i-propyl)phenyl]ethylamine, and 1.21 g of triethylamine in 100 mL of ethanol was heated at reflux for one hour. The ethanol was removed and the remaining product was dissolved in 100 mL of methylenechloride and then washed with aqueous sodium carbonate. The organic layer was then dried and the solvent was removed. The residue was slurried in pentane. Yield: 2.4 g. M.P. 170°-172° C.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][S:13][C:4]1[N:3]=[C:2]([NH:26][CH2:25][CH2:23][OH:24])[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=1
Reactant: NCCO
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Product: O=c1cnc2c(NCCO)nc(SCc3cccc(F)c3F)nc2[nH]1

Procedure:
The titled compound (52 mg) was prepared from the product of Example 3 step (b) (150 mg) and ethanolamine (35 ul) using the method of Example 2 step (f).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:44][C:45]([CH3:65])=[CH:46][CH2:47][CH2:48]/[C:49](/[CH3:64])=[CH:50]/[CH2:51][CH2:52]/[C:53](/[CH3:63])=[CH:54]/[CH2:55][S:56][CH2:57][C@H:58]([NH2:62])[C:59]([OH:61])=[O:60]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([C:8](=[O:10])[NH:62][CH:58]([C:59]([OH:61])=[O:60])[CH2:57][S:56][CH2:55][CH:54]=[C:53]([CH3:63])[CH2:52][CH2:51][CH:50]=[C:49]([CH3:64])[CH2:48][CH2:47][CH:46]=[C:45]([CH3:65])[CH3:44])[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1(C(=O)NC(CSCC=C(C)CCC=C(C)CCC=C(C)C)C(=O)O)CC1
Temperature: 25 °C

Procedure:
In a 100 mL round bottom flask, 1,1-Cyclopropanedicarboxylic acid monomethyl ester (158 mg, 1.1 mmol), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 mg, 1.1 mmol) and N,N-diisopropyl-ethyl-amine (0.52 mL, 3 mmol) were mixed in THF (5 mL). The reaction solution was stirred at room temperature for ten minutes. S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) was added to reaction mixture. The reaction solution was stirred at room temperature overnight. Ethyl acetate (50 mL) was added and then washed with saturated ammonium chloride aqueous solution (20 mL×2), DI water (20 mL×2) and brine (20 mL×2) sequentially. The ethyl acetate solution was dried by Na2SO4 and concentrated in vacuo to afford crude Compound N-52. The crude Compound N-52 was purified by HPLC (120 mg, 27%) to yield Compound N-52. 1H-NMR (500 MHz, MeOH-d4): δ 1.45-1.48 (m, 4H), 1.50 (s, 6H), 1.57 (s, 3H), 1.58 (s, 3H), 1.85-1.89 (m, 2H), 1.93-1.98 (m, 4H), 2.01-2.05 (m, 2H), 2.78-2.91 (m, 2H), 3.06-3.15 (m, 2H), 3.62 (s, 3H), 4.56 (t, J=5.0 Hz, 1H), 4.97-5.02 (m, 2H), 5.12 (t, J=7.5 Hz, 1H). 13C-NMR (125 MHz, MeOH-d4): δ 9.2, 16.14, 16.20, 17.80, 20.05, 25.95, 27.31, 27.37, 27.78, 30.61, 33.62, 40.74, 40.88, 52.96, 53.97, 121.61, 125.11, 125.45, 132.11, 136.28, 140.59, 170.81, 173.75, 174.39; ES-MS: mass calcd for Chemical Formula: C24H37NO5S 451.2. Found (M+Na) m/z 474.2.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][C:9]([CH3:11])=[CH2:10])=[C:6]([CH3:12])[C:5]([NH:13][CH:14]=[O:15])=[C:4]([CH3:16])[C:3]=1[CH3:17].C(=O)([O-])[O-].[Ca+2].I(Cl)(=O)=O.[I:27](Cl)(=O)=O.[CH2:31]([N+](C)(C)C)[C:32]1[CH:37]=CC=CC=1>O1CCCC1.CO>[I:27][CH2:10][C:9]1([CH3:11])[CH2:8][C:7]2[C:6]([CH3:12])=[C:5]([NH:13][CH:14]=[O:15])[CH:4]([CH3:16])[C:3]([CH:32]([CH3:37])[CH3:31])([CH3:17])[C:2]=2[O:1]1
Reactant: O=I(=O)Cl
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: C=C(C)Cc1c(C)c(NC=O)c(C)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=C(NC=O)C(C)C(C)(C(C)C)C2=C1CC(C)(CI)O2
Reaction time: 0.17 h
Yield: 118 %

Procedure:
To a suspension of N-[4-hydroxy-2,3,6-trimethyl-5-(2-methyl-2-propenyl)phenyl]formamide (187 g) and calcium carbonate (104 g) in tetrahydrofuran (600 mL) and methanol (600 mL) was added benzyltrimethylammonium dichloroiodate (307 g) slowly. The mixture was stirred for 10 minutes. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo. To the residue was added ethyl acetate (800 mL) and water (400 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (400 mL). The combined organic layer was washed with 10% aqueous solution hydrogen sulfite (400 g), water (300 mL), saturated aqueous sodium bicarbonate (300 mL) and aqueous sodium chloride (300 mL). The organic layer was dried over magnesium sulfate, treated with activated carbon, filtrated and the filtrate was concentrated in vacuo. The residue was crystallized from ethyl acetate/diisopropyl ether to afford 271 g of the title compound. Yield 94%.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)=O.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][C:34]([NH2:37])([CH3:36])[CH3:35].N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1>>[ClH:23].[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[CH:32][CH:31]=2)[C:27]([CH2:33][C:34]([NH:37][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([CH3:35])[CH3:36])=[CH:28]1
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Reactant: CS(=O)(=O)OCCOc1ccccc1OCc1ccccc1
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Product: CC(C)(Cc1c[nH]c2ccccc12)NCCOc1ccccc1OCc1ccccc1
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-(2-benzyloxyphenoxy)ethyl methanesulfonate and [2- (5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(1H-indol-3yl)-1,1-dimethylethyl]amine, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl]{2- (2-benzyloxyphenoxy)ethyl}amine hydrochloride, m.p. 148°-150° C.
Reaction SMILES: [Co:1].[N+:2]([O-:5])([OH:4])=[O:3].[N+:6]([O-:9])([O-:8])=[O:7].[Co+2].[N+]([O-])([O-])=[O:12]>>[N+:2]([O-:5])([O-:4])=[O:3].[Co+2:1].[N+:6]([O-:9])([O-:8])=[O:7].[Co:1]=[O:12]
Reactant: O=[N+]([O-])O
Reactant: [Co]
Agent: [Co+2]
Agent: O=[N+]([O-])[O-]
Product: O=[Co]
Temperature: 500 °C

Procedure:
A concentrated cobalt nitrate solution is prepared by reacting 255 parts of electrolytic grade cobalt with 2,060 parts of 40 percent nitric acid. About 5 percent of the concentrated cobalt nitrate solution is reserved for later use in this example as described below. The remainder of the solution is reduced in volume by evaporation and transferred to an aluminum pan. The highly concentrated cobalt nitrate solution is heated in a furnace at 500° C. for 4 hours to form a first porous mass of cobalt oxide. The decomposition of the nitrate begins in solution and no crystals of cobalt nitrate are observed to form. This porous mass is cooled to ambient temperature and saturated with the portion of cobalt nitrate solution previously reserved. Then, the saturated mass is heated in the furnace at 500° C. for 4 hours to produce a second porous mass of cobalt oxide, consisting essentially of Co3O4 and containing 48.9 percent trivalent cobalt, Co+3. This second porous mass of cobalt oxide is cooled to ambient temperature, ground, and screened to provide a particulate cobalt oxide catalyst having a specific surface area of 0.2 m2 /g and a bulk density of 1.7 g./ml. The catalyst is in the form of irregular particles of length and mean diameter about equal and in the range 1.4 to 4.0 mm., said particles having a mean crushing strength of 4,200 grams per particle.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](O)=[O:9])=[N:6][N:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)[C:4]2[N:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.C(Cl)(=O)OC(C)C.[CH:35]1([NH2:38])[CH2:37][CH2:36]1>C(Cl)Cl>[CH:35]1([NH:38][C:8]([C:7]2[C:2](=[O:1])[C:3]3[CH:27]=[CH:26][CH:25]=[N:24][C:4]=3[N:5]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:12]=3)[N:6]=2)=[O:9])[CH2:37][CH2:36]1
Reactant: NC1CC1
Reactant: O=C(O)c1nn(-c2cccc(Sc3cccnc3)c2)c2ncccc2c1=O
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Product: O=C(NC1CC1)c1nn(-c2cccc(Sc3cccnc3)c2)c2ncccc2c1=O
Yield: 6.3 %

Procedure:
4-oxo-1-(3-(pyridin-3-ylthio)phenyl)-1,4-dihydropyridino[2,3-c]pyridazine-3-carboxylic acid (200 mg, 0.53 mmol) was dissolved in 100 ml of DCM, the following were added dropwise at −15° C. in order: TEA (133.8 mg, 1.325 mmol), isopropyl chlorocarbonate (97 mg, 0.792 mmol), and reacted at −15° C. for 0.5 h, then cyclopropylamine (36 mg, 0.631 mmol) was added dropwise, reacted at room temperature for 3 h. The reaction solution was washed with water, the organic phase was dried, concentrated and crystallized to obtain an object product 13.78 mg.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[OH-].[Na+].[CH2:19]=O.[C:21]1([S:27]([O-:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na+].Cl>O.C1(C)C=CC=CC=1>[OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[CH2:19][S:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:29])=[O:28]
Reactant: C=O
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Reactant: O=S([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=S(=O)(Cc1c(C(F)(F)F)nn(-c2ccccc2)c1O)c1ccccc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
5-Hydroxy-1-phenyl-3-trifluoromethylpyrazole (2.3 g (10 mmol)) synthesized in Reference Example 2 and 0.6 g (15 mmol) of sodium hydroxide were dissolved in 10 mL of water. While stirring the resulting solution at room temperature, 1.7 g (20 mmol) of a 35% formalin solution was added dropwise thereto, followed by stirring at the same temperature for 1 hour. Subsequently, 1.6 g (10 mmol) of sodium benzenesulfinate was charged thereto at room temperature, and the obtained mixture was stirred for 2 hours. After the reaction, 6.0 g (60 mmol) of 35% hydrochloric acid was added dropwise thereto, and the toluene layer obtained from an extraction operation performed twice with 20 mL of toluene was washed with 10 mL of water and then with 10 mL of saturated brine and dried over anhydrous sodium sulfate. Thereafter, toluene was removed by distillation under reduced pressure to obtain 3.4 g (yield: 88.1%) of the title compound as a viscous material. This viscous material was left standing at room temperature for 2 days and thereby crystallized.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]([CH3:12])[CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C([Li])CCC.CC1CCCO1.[CH3:24][O:25][C:26]([C:28]1[C:36]2[C:31](=[CH:32][C:33]([Cl:38])=[C:34](Br)[CH:35]=2)[N:30]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH:29]=1)=[O:27]>C1COCC1.CC(C)=O.[Cl-].[Cl-].[Zn+2]>[CH3:24][O:25][C:26]([C:28]1[C:36]2[C:31](=[CH:32][C:33]([Cl:38])=[C:34]([C:2]3[C:7]([O:8][CH3:9])=[N:6][C:5]([N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=3)[CH:35]=2)[N:30]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH:29]=1)=[O:27]
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(Cl)c(Br)cc12
Reactant: COc1nc(N(C)C)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: COC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(Cl)c(-c3ccc(N(C)C)nc3OC)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of Intermediate (5-bromo-6-methoxy-pyridin-2-yl)dimethyl-amine (78.8 g, 341 mmol) in THF (400 mL) at −70° C. was added a solution of n-butyllithium (2.5 M in hexanes, 127 mL, 317 mmol) dropwise, keeping the internal temperature below −60° C. The purple solution was stirred between −65° C. and −70° C. for 20 min. A solution of ZnCl2 in 2-methyltetrahydrofuran (1.9 M, 167 mL, 317 mmol) was added dropwise to the aryl lithium solution, keeping the internal temperature below −60° C. The resulting mixture was stirred between −65° C. and −70° C. for 20 min and then warmed to room temperature and stirred for 2 h, resulting in a clear pale yellow solution. The aryl zinc solution was then cannulated into a flask containing Intermediate 5-bromo-6-chloro-1-(toluene-4-sulfonyl)-1H-indole-3-carboxylic acid methyl ester (107.8 g, 244 mmol) and dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (8.72 g, 12.2 mmol) in THF (200 mL). The resulting mixture was stirred at room temperature for 2.5 h before quenching with sat. aq. NH4Cl (800 mL) and extracting with ethyl acetate (1500 mL). The aqueous layer was back extracted with ethyl acetate (750 mL) and the combined organics washed with brine (1000 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with methanol (˜600 mL) and stirred overnight. The suspension was filtered to give a tan solid. This was dissolved in hot acetone (2 L) which was partially concentrated to ˜500 mL, then slowly cooled and stirred overnight. The resulting solid was filtered to yield one crop of desired product (109.1 g). The filtrate was also concentrated to a dark solid which was slurried in acetone, filtered, and the solid dissolved in hot acetone, which was then cooled to yield a second crop (3.3 g) of desired product as an off white solid. (90% total yield). 1H NMR (DMSO-d6, 400 MHz) δ=8.51 (s, 1H), 8.11 (d, J=8.6 Hz, 2H), 8.00 (s, 1H), 7.88 (s, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 1H), 6.22 (d, J=8.2 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.06 (s, 6H), 2.37 (s, 3H); MS (ES+) 514.2 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:6]=[N:7][C:8](Cl)=[N:9][CH:10]=1>CN(C)C=O.O>[Br:4][C:5]1[CH:6]=[N:7][C:8]([C:1]#[N:2])=[N:9][CH:10]=1
Reactant: [C-]#N
Reactant: Clc1ncc(Br)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium cyanide (2.30 g, 46.6 mmol) was dissolved in dimethylformamide (60 ml) and treated with 5-bromo-2-chloropyrimidine (6.0 g, 31.1 mmol). The resulting mixture was stirred at room temperature for 18 hours, diluted with water and extracted with dichloromethane. The dichloromethane extracts were combined, washed with water, dried (magnesium sulphate), filtered and concentrated in vacuo. The crude product was purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:4) to afford the title compound (D38).